Field of the Invention
The present invention relates to microparticles containing physiologically active peptides, a method for preparing the same, and a pharmaceutical composition comprising the same. More specifically, the present invention relates to microparticles which comprise an ionic complex of physiologically active peptide and water-soluble polymer, and a biodegradable water-insoluble polymer, and thus can reduce initial burst of peptide drugs and control the release rate, by which the therapeutic effects of drugs can be improved; a method for preparing the same; and a pharmaceutical composition comprising the same for peptide drugs.
Description of the Related Art
Conventional formulations for injection such as infusion solutions, suspensions and emulsions are rapidly removed from the body after they are intramuscularly or subcutaneously administered. For this reason, frequent administration by injection is required for treatment of chronic diseases. In an attempt to solve this problem, microencapsulation—a process in which a drug is encapsulated into microspheres—has been suggested. Microspheres are produced in a size of unit of several μm to several tens of and thus can be injected intramuscularly or subcutaneously. Accordingly, they can control the drug release rate and thus can adjust the drug delivery period. Therefore, a therapeutically effective drug concentration can be maintained for a long period of time by a single administration.
Generally, after oral administration, most peptide drugs lose their active structures or are broken down by enzymatic degradation under acidic environments, and are poorly absorbed in the gastric or intestinal mucosa. For this reason, peptide drugs are administered by injection. Peptide drugs should be injected continuously and repeatedly because of their short half-life and low bioavailability in vivo. It is also frequently required to administer peptide drugs for a long period of several months. Accordingly, a great deal of research on sustained and controlled release formulations using biodegradable polymers is actively underway.
Aliphatic polyesters have been developed and their bioavailability has been approved by the U.S. Food and Drug Administration (U. S. FDA), and they are currently used as polymeric carriers for peptide drugs. Aliphatic polyesters are widely utilized in applications including carriers for drug delivery, surgical sutures and the like.
Recently, physiologically active peptides have been developed as novel drugs and thus a variety of approaches to continuously release the drugs by encapsulating these drugs in polymer carriers has been conducted. However, such formulations where peptide drugs are encapsulated in microspheres comprising an aliphatic polyester, have disadvantages including initial burst (excessive release) effect of drugs, difficulty in maintaining the drug release rate constantly for a predetermined period of time, and incomplete release, i.e., the release of less than 100% of the encapsulated drug. The initial burst of drug is due to the fact that peptide drugs adsorbed on the surface and pores of microspheres are rapidly diffused and released at an initial stage. Accordingly, there is a demand for a method for preparing sustained-release microspheres containing peptide, by which the initial burst of drugs is avoided and 100% of the encapsulated drug is released at a zero-order rate during the release period of time. It is also required that the method is simple, the encapsulation ratio of the drug is high, the encapsulated drug is highly stable and the method is economically efficient.
It has been known that the methods for preparing drug-containing microspheres include phase separation, melt-extrusion, followed by cryopulverization, double emulsion evaporation (W/O/W, water/oil/water), single emulsion evaporation (O/W, oil/water), spray drying and the like.
The phase separation disclosed in U.S. Pat. No. 4,673,595 is a method for preparing microparticles by dissolving a polymer in methylene chloride. This method uses methylene chloride in combination with silicone oil, ethyl alcohol, etc., and thus has a disadvantage of the complicated overall process to remove all of the used organic solvents.
U.S. Pat. No. 5,134,122 discloses the melt extrusion followed by cryopulverization. This method is free from the risk of residual toxic solvents since no toxic solvent is used in the preparation process. However, peptides may be denatured due to the heat generated during the grinding procedures to obtain PLGA microparticles and peptide microparticles. It is also difficult to control the size of the obtained microparticles to a level suitable for easy injection.
The emulsion evaporation (W/O/W) is generally used. U.S. Pat. No. 5,271,945 discloses a method in which an aqueous solution containing a peptide is dispersed in an organic solvent containing a biodegradable polymer to form a primary emulsion (W/O) and the primary emulsion is then dispersed in an aqueous phase containing an emulsifying agent. However, when microparticles are prepared by such emulsion evaporation, the microparticles may exhibit different biological response levels due to the wide range of particle size distribution and thus it is difficult to predict pharmaceutical effects. Furthermore, it is difficult to develop clinically useful carriers due to the existence of the particles much bigger than the average size.
In addition, since most bio-peptide drugs are water-soluble, said methods have disadvantages in that a considerable amount of drugs escapes in the aqueous phase during the dispersing process and thus the encapsulation ratio becomes low.